Silvated prostaglandins and process therefor

ABSTRACT

SILYLATED INTERMEDIATES USEFUL FOR PREPARING PROSTAGLANDIN-TYPE COMPOUNDS WITH A METHYL OR AN ETHYL SUBSTITUENT AT C-15. THE END PRODUCTS ARE USEFUL FOR THE SAME PHARAMCOLOGICAL PURPOSES AS THE UNSUBSTITUTED PROSTAGLANDINS.

United States Patent 01 ice 3,770,788 Patented Nov. 6, 1973 US. Cl. 260-448.8 R 20 Claims ABSTRACT OF THE DISCLOSURE Silylated intermediates useful for preparing prostaglandin-type compounds with a methyl or an ethyl substituent at C-15. The end products are useful for the same pharmacological purposes as the unsubstituted prostaglandins.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of my copending application Ser. No. 34,518 filed May 4, 1970.

DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter, to novel methods for producing those, and to novel chemical intermediates useful in those processes. In particular, this invention relates to novel derivatives of prostanoic acid which the following structure and atom numbering:

I C O OH (PGE has the following structure:

Prostaglandin E (PGE has the following structure:

H0 H 011 (III) Prostaglandin E (PGE has the following structure:

Dihydroprostaglandin E (dihydro-PGE has the following structure:

COOH

Prostaglandins with a secondary alpha or beta hydroxy in place of the ring oxo of the prostaglandins E are also known. These are called prostaglandins F. For example, prostaglandin F (PGF has the following structure:

COOH

H0 11 on (V1) Prostaglandin F (PGF has the following structure:

HO OH (v11) Prostaglandins F, and F, corresponding to PGE PGE and dihydro-PGE, are also known.

In Formulas II to VII, broken line attachments to the cyclopentane ring indicate snbstituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The side-chain hydroxy at C-15 in Formulas II to VII is in S configuration. See Nature, 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.

Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e., the dextrorotatory and levorotator forms. As drawn, Formulas II to VII each represent the particular optically active form of the prostaglandin which is obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, or by carbonyl and/or double bond reduction of a prostaglandin so obtained. See, for example, Bergstrom et al., cited above. The mirror image of each of Formulas II to VII would represent the other enantiorner of that prostaglandin. The racemic form of a prostaglandin would contain equal numbers of both enantiomeric molecules, and one of Formulas II to VII and the mirror image of that formula would both be needed to represent correctly the corresponding racemic prostaglandin. For convenience hereinafter, use of the terms PGE1, PGEZ, PGE3, P lm PGFz PGF3m dihydro-PGF PGF PGF PGF and dihydro-PGF will mean the optically active form of that prostaglandin with the same absolute configuration as PGE obtained from mammalian tissues. When reference to the racemic form of one of those prostaglandins is intended, the word racemic will proceed the prostaglandin name, thus, racemic PGE or racemic PGF Each of the novel prostanoic acid derivatives of this invention is encompassed by one of the following formulas or by the combination of that formula and its mirror image:

(VIII) HO a. on (IX) X\ Y \MCOORI E E1 OH (x) HO R; on (XI) coona. on (mm In Formulas VIII to XIII, R is hydrogen, alkyl of one to 8 carbon atoms, inclusive, or a pharmacologically acceptable cation, R is methyl or ethyl, and X is oxo, alpha hydroxy, or beta hydroxy, i.e., =0,

H n r In Formulas VIII, X, and XII, the configuration of the hydroxy at C-l5 is S as in the known prostaglandins of Formulas II to VII. In Formulas IX, XI, and XIII, the hydroxy at C- is in the unnatural R configuration. See J. Chem. Education, 41, 116 (1964), for discussion of S and R configurations.

A significant characteristic of all the known prostaglandins is the secondary hydroxy group at C-15, i.e., the atom grouping n on Prostaglandins obtained from animal tissues always con tain that atom grouping. In striking contrast, each of the or the corresponding R configuration grouping in OH wherein R is methyl or ethyl. Thus, these novel prostanoic acid derivatives may conveniently be designated IS-methyl-prostaglandis or IS-ethyl-prostaglandins, e.g., 15methyl-PGE l5-ethyl-PGF a, and l5-methyll5(R)-PGF 9.

As in the case of Formula II to VII, Formulas VIII to XIII are each intended to represent optically active prostanoic acid derivatives, having, except for the hydroxy at C9 or C-lS in certain compounds, the same absolute configuration as PGE obtained from mammalian tissues. In addition, the novel prostanoic acid derivatives of this invention also include the corresponding racemic compounds. One of Formulas VIII-XIII, inclusive, plus the mirror image of that formula are necessary in combination to describe a racemic compound. For convenience hereinafter, when the word racemic precedes the name of one of the novel prostanoic acid derivatives of this invention, the intent is to designate a racemic compound represented by the combination of the appropriate Formula VIII to XIII and the mirror image of that formula. When the Word racemic does not precede the compound name, the intent is to designate an optically active compound represented only by the appro riate Formula VIII to XIII and with the same absoluble configuration as PGE obtained from animal tissues.

PGE PGE PGE dihydro-PGE and the corresponding PGFu and PFGB compounds, and their esters and pharmacologically acceptable salts are extremely potent in causin various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGE and PGFfl compounds as measured, for example, in anesthetized (pentobarbital sodium) pentolinium-treated rates with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for the PGFa compounds; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isloated rat fat pads; inhibition of gastric secretion in the case of the PGE compounds as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various bicohemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen; and in the case of the PGE compounds, stimulation of epidermal proliferation and keratinization as shOWn when applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially the PGE compounds, are useful in mammals, including man, as

nasal decongestants. For this purpose, the compounds are used in a dosage range of about g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The PGE compounds are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby re ducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 g. to about 500 g. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGE, PGF,,, and PGF, compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGE, PGF,, and PGF, compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about .001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range of 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The PGE and PGF, compounds are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 g. per kg. of body weight per minute, or in single or multiple doses of about 25 to 500 g. per kg. of body weight total per day.

The PGE, PGF,,, and PGF, compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose 0.01 to 50 g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started.

The PGF,, PFG and PGE compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. For that purpose, PGE or PGF for example, is administered systemically, e.g., intravenously, subcutaneously, and intravaginally, at a dose level in the range of 0.001 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approxi mately at the next expected time of menses or just prior to that time. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.

As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases, involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.

The novel IS-methyl and IS-ethyl prostaglandin analogs encompassed by formulas VIII to XIII, the corresponding R and S IS-methyl and 15-ethyl PGE PGF and PGF compounds, and also the corresponding racemic analogs each cause the same biological responses described above for the corresponding known prostaglandins. Each of these IS-methyl and IS-ethyl compounds is accordingly useful for the above-described pharmacological purposes, and is used for those purposes as described above. However, each of these IS-methyl and IS-ethyl prostaglandin analogs is surprisingly and unexpectedly more useful than the corresponding known prostaglandin for at least one of the pharmacological purposes described above because for that purpose the analog is more potent and has a substantially longer duration of activity. For that reason, fewer and smaller doses of these prostaglandin analogs are needed to attain the desired pharmacological results.

The novel PGE-type, PGE-type, and PGF -type analogs encompassed by formulas VIII to XIII, the corresponding R and S PGE PGF and PGF analogs, and also the corresponding racemic analogs are used as described above in free acid form, in alkyl ester form, or in pharmacologically acceptable salt form. When the ester form is used, any alkyl ester can be used wherein the alkyl moiety contains one to 8 carbon atoms, inclusive, i.e., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,

and isomeric forms thereof. However, it is preferred that the ester be alkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.

Pharmacologically acceptable salts of these prostaglandin analogs useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, e g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically aceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of sutiable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, tit-phenylethylamine, B-phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, Z-methylpyrrolidine, 1,4- dimethylpiperazine, Z-methylpiperidine, and the like, as Well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, Z-amino-l-butanol, 2 amino 2-ethyl-l,3-propanediol, Z-amino-Z-methyl-lpropanol, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N (p tert-amylphenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, phenyltriethylarnmonium, and the like.

As discussed above, the prostaglandin analogs are administered in various Ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility to use the free acid form or the pharmacologically acceptable salt form. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories, tampons, ring devices, and preparations adapted to generate sprays of foams or to be used for lavage, all prepared as known in the art used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.

The novel PGE-type acids and alkyl esters of Formulas VIII to XIII wherein X is =0, and also the corresponding R and S PGE -type acids and alkyl esters are prepared by oxidation of the corresponding PGF -type or P6P,- type acids and alkyl esters. For this purpose, an oxidizing agent is used which selectively oxidizes secondary hydroxy groups to carbonyl groups in the presence of carbon-carbon double bonds. These transformations are shown in Chart A, wherein the formulas as drawn represent optically active compounds. When the same process steps are applied to the corresponding racemic starting materials consisting of the optically active compounds as depicted and the mirror images thereof, those process steps yield the corresponding racemic intermediates or racemic prostaglandin analogs. Likewise, the corresponding 15- epimeric starting materials of either the optically active compounds or their racemates yield the corresponding 15- epimeric products. Also in Chart A, R is methyl or ethyl, R, is hydrogen or alkyl of one to -8 carbon atoms, inclusive, X and Y are both CH CH or X is trans CH=CH and Y is -CH CH or cisCH=CH, and indicates attachment of hydroxy to the ring in alpha or beta configuration.

For the transformations of Chart A, the beta isomers of reactants XIV and XVI are preferred starting materials, although the corresponding alpha isomers are also useful for this purpose.

Oxidation reagents useful for the transformations set forth in Chart A are known to the art. An especially useful reagent for this purpose is the Jones reagent, i.e., acidified chromic acid. See J. Chem. Soc. 39 (1946). Acetone is a suitable diluent for this purpose, and a slight excess beyond the amount necessary to oxidize one of the secondary hydroxy groups of the Formula XIV or XVI reactant is used. Reaction temperatures at least as low as about 0 C. should be used. Preferred reaction temperatures are in the range l'0 to -50 C. The oxidation proceeds rapidly and is usually complete in about 5 to about 20 minutes. The excess oxidant is destroyed, for example, by addition of a lower alkanol, advantageously, isopropyl alcohol, and the Formula XV or XVII PGE-type product is isolated by conventional methods.

Examples of other oxidation reagents useful for the Chart A transformations are silver carbonate on Celite (Chem. Commun. 1102 (1969)), mixtures of chromium trioxide and pyridine (Tetrahedron Letters 3363 (1968),

J. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351 (1962)), mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide (I. Am. Chem. Soc. 89, 5505 (1967)), and mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87, 5661 (1965)).

The novel PGF -type and PGF -type acids and esters of Formulas VHI to X=III wherein'X is H 11 of 1 transCH=CI-I and Y is cisCH- CH and indicates attachment of hydroxy to the ring in alpha or beta configuration. Also in Charts B and C, A is alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, and R is alkyl of one to 8 carbon atoms, inclusive, or Si(A) wherein A is as defined above.

CHART B 1 O I l The various A of a -Si(A) moiety are alike or dififerent. For example, an Si(A) can be trimethylsilyl, di-

methylphenylsilyl, or methylphenylbenzylsilyl. Examples of alkyl of one to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, u-phenylethyl, 3-phenylpropyl, u-naphthylmethyl, and Z-(B-naphthyDethyl. Examples of phenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, m-fiuorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

In Charts B and C, the final PGF and PGF products are those encompassed by Formulas XX-I-l-XXII and XXVI+XXVIL respectively.

The initial optically active reactants of Formulas XVIII and XXIII in Charts B and C, i.e., PGF PGF PGF PGF PGF PGF dihydro-PGF and dihydro-PGF and their alkyl esters are known in the art or are prepared by methods known in the art. See, for example, Bergstrom et al., cited above, US. Pat. No. 3,069,322, and British specification No. 1,040,544. The initial racemic reactants of Formula XVIII in Chart B, i.e., racemic PGF racemic PGF racemic PGF racemic PGF racemic PGF the racemic PGE and their alkyl esters are known in the art or are prepared by methods known in the art. See, for example, Just et al., J. Am. Chem. '91, S364 (1969), Corey et al., J. Am. Chem. Soc. 90, 3245 (1968), Schneider et al., Chemical Communications (Great Britain), 304 1969), and Axen, Chemical Communications, 602 (1970).

Racemic dihydro-PGF and racemic dihydro-PGF and their esters are prepared by catalytic hydrogenation of the corresponding racemic PGF or PGF and PG'F or PGF compounds, respectively, for example, in the presence of palladium-on-charcoal catalyst in ethyl acetate solution at 25 C. and one atmosphere pressure of hydrogen.

The known acids and esters of Formulas XVIII and XXIII are transformed to the corresponding intermediate l5-oxo acids and esters of Formulas XIX and XXIV, respectively, by oxidation with reagents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, activated manganese dioxide, or nickel peroxide (see Fieser et al., Reagents for Oragnic Synthesis," John Wiley and Sons, Inc., New York, N.Y., pp. 215, 637, and 731). Alternatively, and especially for the Formula XVIII reactants wherein X and Y are CH CH these oxidations are carried out by oxygenation in the presence of the IS-hydroxyprostaglandin dehydrogenase of swine lung (see Arkiv for Kemi 25, 293 (1966)). These reagents are used according to procedures known in the art. See, for example, J. Biol. Chem. 239, 4097 (1964).

Referring againt to Charts B and C, the intermediate compounds of Formulas XIX and XXIV are transformed to silyl derivatives of Formulas XX and XXV, respectively, by procedures known in the art. See, for example, Pierce, Silylation of Organic Compounds, Pierce Chemical Co., Rockford, Ill. (1968). Both hydroxy groups of the Formula XIX or XXIV reactants are thereby transformed to -OfiSi(A) moieties wherein A is as defined above, and sufiicient of the silylating agent is used for that purpose according to known procedures. When R in the Formula XIX or XXIV intermediate is hydrogen, the COOH moiety thereby defined is simultaneously transformed to COO--Si-(A) additional silylating agent being used for this purpose. This latter transformation is aided by excess silylating agent and prolonged treatment. When R, in Formulas XIX and XXIV is alkyl, then R in Formulas XX and XXV will also be alkyl. The necessary silylating agents for these transformations are known in the art or are prepared by methods known in the art. See, for example, Post, Silicones and Other Organic Silicon Compounds, Reinhold Publishing Corp., New York, NY. (1949).

Referring again to Charts B and C, the intermediate silyl compounds of Formulas XX and XXV are transformed to the final compounds of Formulas XXI+XXII and XXVI+XXVIL respectively, by first reacting the silyl compound with a Grignard reagent of the Formula R MgX wherein R is methyl or ethyl, and X is chloro, bromo, or iodo. For this purpose, it is preferred that X be bromo. This reaction is carried out by the usual procedure for Grignard reactions, using diethyl ether as a reaction solvent and saturated aqueous ammonium chloride solution to hydrolyze the Grignard complex. The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzed with water to remove the silyl groups. For this purpose, it is advantageous to use a mixture of water and suificient of a water-miscible solvent, e.g., ethanol to give a homogenous reaction mixture. The hydrolysis is usually complete in 2 to 6 hours at 25 C., and is preferably carried out in an atmosphere of an inert gas, e.g., nitrogen or argon.

The mixture of 154 and l'5-R isomers obtained by this Grignard reaction and hydrolysis is separated by procedures known in the art for separating mixtures of prostanoic acid derivatives, for example, by chromatography on neutral silica gel. In some instances, the lower alkyl esters, especially the methyl esters of a pair of 15-8 and l5-R isomers is more readily separated by silica gel chromatography than are the corresponding acids. In those cases, it is advantageous to esterify the mixture of acids as described below, separate the two esters, and then, if desired, saponify the esters by procedures known in the art for saponification of prostaglandins F.

Although Formula XXI and XX'H compounds wherein X and Y are both CH CH are produced according to the processes of Chart B, it is preferred to produce those novel dihydro-PFG analogs by hydrogenation of one of the corresponding unsaturated compounds, i.e., a compound of Formula XXI or XXII wherein X is transCH=CH- and Y is CH CH or ci s-CH CH- or a compound of Formula XXVI or XXVII. This hydrogenation is advantageously carried out catalytically, for example, in the presence of a 5% palladium-oncharcoal catalyst in ethyl acetate solution at 25 C. and one atmosphere pressure of hydrogen.

As discussed above, the processes of Charts A, B, and C lead either to acids (R is hydrogen) or to alkyl esters (R is alkyl of one to 8 carbon atoms, inclusive). When a Formula XXI, XXII, XXVI, XXVII PGF-type acid or a Formula XV or XVII PGE-type acid (Chart A) has been prepared and an alkyl ester is desired, esterification is advantageously accomplished by interaction of the acid with the appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane, and 1-diazo-2-ethylhexane, for example, gives the ethyl, butyl, and Z-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley & Sons, Inc, New York, N.Y., vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moiety of the PGF-type or PGE-type compounds comprises transformation of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tertbutyl iodide, and the like. The silver salts are prepared by conventional methods, for example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of silver nitrate.

The novel Formula VIII to XIII acids (R is hydrogen) are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt of the prostanoic acid derivative. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixing the acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

The invention can be more fully understood by the following examples.

Infrared absorption spectra are recorded on a Perkin- Elmer model 421 infrared spectrophotometer. Undiluted (neat) samples of the liquids and oils are used. Mineral oil (Nujol) mulls of the solids are used.

NMR spectra are recorded on a Varian A-60 spectrophotometer with tetramethylsilane as an internal standard (downfield) and using solvents as indicated below.

Mass spectra are recorded on an Atlas CH-4 mass spectrometer with a TO-4 source (ionization voltage 70 e.v.).

The term -oxoin front of a compound name, e.g., 15 oxo-PGF refers to la protagl'andin analog wherein the moiety 7% H OH at the 15-position has been transformed to EXAMPLE l.15-Oxo-PGF 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (463 mg.) is added to a solution of PGF (600 mg.) in 30 ml. of dioxane. The mixture is stirred 24 hours at 50 C. under nitrogen, and then is cooled to 20 C. and filtered. The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives 650 mg. of a residue which is chromatographed on 150 g. of silica gel (Silicar CC-4; Mallincrodt), eluting with 50% ethyl acetate in Skellysolve B (a mixture of isomeric hexanes). Evaporation of the eluates gives 545 mg. of 15-oxo-PGF infrared absorption at 3400, 2660, 1700, 1660, 1620, 1460, 1410, 1375, 1285, 1250, 1185, 1120, 1070, and 980 cmr' EXAMPLE 2.-15-Oxo-PGF 2,3-dich1oro-5,-6-dicyano-1,4-benzoquinone (1.0 g.) is added to a solution of PGF (1.3 g.) in ml. of dioxane. The mixture is stirred 24 hours at 50 C. under nitrogen, and is then cooled to 20 C. and filtered. The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives 1.6 g. of a residue which is chromatographed on 400 g. of silica gel (Silicar CC-4; Mallincrodt), eluting with 75% ethyl acetate in Skellysolve B. Evaporation of the eluates gives 1.15 g. of 15-oxo-PGF infrared absorption at 3380, 2660, 1720, 1705, 1665, 1620, 1460, 1405, 1370, 1325, 1285, 1235, 1190, 1080, 1040, and 980 cm.-

EXAMPLE 3.15-Oxo-PGF Following the procedure of Example 1, PGF is oxidized to 15-oxo-PGF infrared absorption at 3400, 2660, 1705, 1660, 1625, 1405, 1375, 1320, 1290, 1245-1225, 1215-1175, 1115, 1075, 1050, and 980 cmf EXAMPLE 4.15-Oxo-PGE 1 Following the procedure of Example 1, PGF is oxidized to 15-oxoPGF infrared absorption at 3380, 3010, 2650, 1705, 1655, 1625, 1320, 1295, 1245-1225, 1190, 1085, 1040, and 980 cm.

EXAMPLE 5.-15-Oxo-PGF Following the procedure of Example 1, PGF is oxidized to l5-oxo-PGF Following the procedure of Example, PGF is oxidized to 15-oxo-PGF Also following the procedure of Example 1, the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of PGF PGF PGF PGFg PGF and PGF are each oxidized to the corresponding 15-oxo compounds.

Also following the procedure of Example 1, the racemic forms Of PGFIM PGFIB, PGFQE, PGFZB, P6133, PGF3B, and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those are each oxidized to the corresponding racemic 15-oxo compound.

EXAM PLE 7 .Dihydro- 1 5-0XO-PGF1G Following the procedure of Arkiv for Kemi, 25, 293 (1966), dihydro-PGF is oxidized to dihydro-15-ox0- PGF with the 15-hydroxyprostaglandin dehydrogenase enzyme of swine lung.

Following the procedure of Example 7, dihydro-PGF is oxidized to dihydro-lS-oxo-PGF Also following the procedure of Example 7, the methyl ethyl, tert-butyl, and 2-ethylhexy1 esters of dihydro- PGF and dihydro-PGF are each oxidized to the corresponding 15-oxo compounds.

Also following the procedure of Example 7, the racemic forms of dihydro-PGF dihydro-P-GF and the methyl, ethyl, tert-butyl, and Z-ethylhexyl esters of those are each oxidized to the corresponding racemic 15-oxo compound.

EXAMPLE 8.Tris-(trimethylsilyl) Derivatives of 15-Oxo-PGE A mixture of hexamethyldisilazane (11 ml.) and trimethylchlorosilane (2.2 ml.) is added to a solution of 15 15-oxo-PGF (545 mg.) in 55 ml. of tetrahydrofuran. This mixture is stirred 16 hours at 25 C. under nitrogen, and is then filtered. The filtrate is evaporated under re duced pressure. Xylene (50 ml.) is added to the residue and the mixture is evaporated at 60 C. under reduced pressure. This addition of xylene and evaporation is repeated twice. The resulting residue is the tris-(trimethyl silyl) derivatives of 15-oxo-PGF infrared absorption at 1365, 1250, and 1180 cmf EXAMPLE 9.Tris-(trimethylsilyl) Derivatives of 15-Oxo-PGF Following the procedure of Example 8, l-o-xo-PGF is transformed to the tris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680, 1635, 1375, 1250, 1180, 1065, 980, 840, and 750 cmf EXAMPLE 10.Tris-(trimethylsilyl) Derivative of 15-Oxo-PGF Following the procedure of Example 8, 15-oxo-PGF is transformed to the tris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680, 1635, 1250, and 845 cm.-

EXAMPLE 11.Tris(trimethylsilyl) Derivative of 15-Oxo-PGF Following the procedure of Example 8, 15-oxo-PGF is transformed to the tris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680, 1635, 1250, and 845 CH1.' 1.

EXAMPLE l2.Tris-(trimethylsilyl) Derivative of 15-Oxo-PGF Following the procedure of Example 8, 15-oxo-PGF is transformed to the tris-(trimethylsilyl) derivative.

EXAMPLE l3.-Tris-(trimethylsilyl) Derivative of 15-Oxo-PGF Following the procedure of Example 8, 15-oxo-PGF is transfermed to the tris-(trimethylsilyl) derivative.

EXAMPLE l4.Tris-(trimethylsilyl) Derivative of Dihydro-lS-oxoPGF Following the procedure of Example 8, dihydro-lS-oxo- PGF is transformed to the tris-(trimethylsilyl) derivative.

EXAMPLE 14A.-Tris-(trimethylsilyl) Derivative of Dihydro-lS-oxo-PGF Following the procedure of Example 8, dihydro-lS-oxo- PGF is transformed to the tris-(trimethylsilyl) derivative.

Following the procedure of Example 8, the methyl, ethyl, tert-butyl, and Z-ethyl-hexyl esters of 15-oxo- PGF 15-oxo-PGF 15-oxo-PGF 15-oxoPGF 15- oxo-PGF 15-oxo-PGF dihydro-15-oxo-PGF and dihydro-lS-oxo-PGF are each transformed to the corresponding bis-(trimethylsilyl) derivative.

Also following the procedure of Example 8, the racemic forms of 15-oxo-PGF 15-oxo-PGF,,, 15-oxo-PGF 15-oxo-PGF 15-oxo-PGF 15-oxo-PGF dihydro-lS- oxo-PGF dihydro-lS-oxo-PGF and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those are each transformed to trimethylsilyl derivatives, the acids to tris derivatives and the esters to his derivative.

Also following the procedure of Example 8 but using appropriate reactants in place of the hexamethyldisilazane and trimethylchlorosilane, there are prepared the tris- (triphenylsilyl) and tris-(tribenzylsilyl) derivatives of 15- oxo-PGF 15-oxo-PGF l5-oxo-PGFza, 15-oxo-PGF l5-oxo-PGF 15-oxo-PGF dihydro-lS-oxo-PGF and dihydro-15-oxo-PGF and of the racemic forms of each of those acids, and also the bis-triphenylsilyl) and bis- (tribenzylsilyl) derivatives of the corresponding methyl, ethyl, tert-butyl, and Z-ethylhexyl esters of each of those optically active and racemic acids.

16 EXAMPLE l5.--15-methyl-PGF and 15-methyl- 15 (R) -PGF A 3 molar diethyl other solution of methylmagnesium bromide (0.55 ml.) is added dropwise to a stirred solution of the tris-(trimethyl) derivative of 15-oxo-PGF (850 mg.) in 25 ml. of diethyl ether at 25 C. The mixture is stirred 30 minutes at 25 C., after which an additional 0.2 ml. of the methylmagnesium bromide solution is added and stirring is continued an additional 30 minutes. The resulting reaction mixture is poured into 75 ml. of saturated aqueous ammonium chloride solution at 0 C. After stirring several minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether gives a yellow oil (910 mg.) which is dissolved in 45 ml. of ethanol. That solution is diluted with 30 ml. of water, and the mixture is stirred 4 hours at 25 C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is saturated with sodium chloride and then extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to give 640 mg. of a mixture of 15-methyl-PGF an 15-methyl-15(R)-PGF infrared absorption at 3280, 2600, and 1710 cmf The mixture of 15-methyl-PGF and 15-methyl-15(R)- PGF is dissolved in 50 ml. of diethyl ether and cooled to 0 C. Excess diazomethane dissolved in diethyl ether is then added, and the mixture is maintained 5 minutes at 0 C. and then 5 minutes at 25 C. The solution is evaporated in a stream of nitrogen, and the residue is chromatographed on 550 g. of neutral silica, eluting with 75% ethyl acetate in Skellysolve B. Evaporation of eluate fractions gives successively, 127 mg. of 15-methy1-15(R)-PGF methyl ester, mg. of a mixture of 15-methyl-15(R)- PGF methyl ester and IS-methyL-PGF methyl ester, and 228 mg. of 15-methyl-PGF methyl ester. The latter crystallizes on standing; M.P. 7275 (3.; mass spectral molecular ion peaks at 366, 348, 317, 313, and 294.

Aqueous potassium hydroxide solution (45%; 0.9 ml.) is added to a solution of IS-methyI-PGF methyl ester (228 mg.) in a mixture of 6.8 ml. of methanol and 2.2 ml. of water under nitrogen. The resulting solution is stirred 2 hours at 25 C., and is then poured into several volumes of water. The aqueous mixture is extracted with ethyl acetate, acidified with 3 N hydrochloric acid, saturated with sodium chloride, and then extracted repeatedly with ethyl acetate. The latter ethyl acetate extracts are combined, washed successively with water and saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of ethyl acetate and Skellysolve B to give 15-methyl-PGF M.P. 81-83 (1.; infrared absorption at 3410, 3300, 2650, 1705, 1305, i290, 1275, 1255, 1220, 1195, 1125, 1075, 980, and 915 cmr NMR peaks (dimethylformamide) at 5.5 and 4.4-3.6 (multiplet) 6; mass spectral molecular ion peaks at 643, 587, and 568.

Following the above procedure, 15-methyl-15(R)- PGF methyl ester is saponified to 15-methyl-15(R)- PGF infrared absorption at 3380, 2650, 1710, 1460, 1410, 1375, 1275-1200, 1125, 1075, 1040, and 975 cmr NMR peaks (dimethylformamide) at 5.50 and 4.40-3.60 (multiplet) 6; mass spectral molecular ion peaks at 352, 334, 316, and 263.

EXAMPLE 16.15-methyl-PGF and IS-methyl 15(R)-PGF1,,

A 3 molar diethyl ether solution of methylmagnesium bromide (0.67 ml.) is added dropwise to a stirred solution of the tris-(trimethylsilyl) derivative of 15-oxo-PGF (910 mg.) in 25 ml. of diethyl ether at 25 C. The mixture is stirred 30 minutes at 25 C., after which an additional 0.3 ml. of the methylmagnesium bromide solution is added and stirring is continued an additional minutes. The resulting reaction mixture is poured into a mixture of ice and 75 ml. of saturated aqueous ammonium chloride solution. After stirring several minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with satunated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether at reduced pressure gives a colorless, viscous oil which is dissolved in 30 ml. of ethanol. That solution is diluted with ml. of water, and the mixture is stirred 3 hours at C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is diluted with an equal volume of saturated aqueous sodium chloride solution and then extracted repeatedly with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure to give 700 mg. of a crystalline mixture of 15-met-hyl-PGF and 15-methyl-15 (R)-PGF Recrystallization of this mixture three times from ethyl acetate containing a trace of methanol gives IS-methyl-PGF M.P. 164-164.5 C.; infrared absorption at 3250, 3160, 2700, 1710, 1330, 1315, 1305, 1085, 1035, and 970 cmr NMR peaks (dimethylformamide) at 5.53 (doublet), 5.10-3.6 (multiplet), and 1.20 (singlet) 6; mass spectral molecular ion peaks at 370, 352, and 334.

15-methyl-15(R)-PGF is obtained from the above-described recrystallization mother liquors.

EXAMPLE 17.-15-methyl-PGF and 15-methy1- 15 (R -PGF Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of 15-oxo-PGF (500 mg.) is transformed first to a mixture of IS-methyI-PGF and 15- methyl-15(R)-PGF and then to the corresponding mixture of methyl esters. This methyl ester mixture (520 mg.) is chrom-atographed on 500 g. of neutral silica gel (Merck), eluting successively with 2 l. of 20%, 6 l. of 40%, and 8 l. of 50% ethyl acetate in Skellysolve, B. The corresponding eluates emerging from the column are discarded. Elution is continued successively with gradients of 4 l. of 50% and 4 l. of 60% ethyl acetate in Skellysolve B, and 5 l. of 60% and 5 l. of 75% ethyl acetate in Skellysolve B, and then with 4 l. of 75 ethyl acetat ein Skellysolve B, collecting the corresponding eluates in 500-ml. fractions. Elution is further continued successively with 5 l. of 75% ethyl acetate in Skellysolve B and with 6 l. of 100% ethyl acetate, collecting the corresponding eluates in 200- ml. fractions. Eluate fractions 29-35 are combined and evaporated to give 109 mg. of 15-methyl-l5(R)-PGF methyl ester. Eluate fractions 39-67 are combined and evtaporated to give 155 mg. of l5-methyl-PGF meth'yl es er.

Following the procedure of Example 15, IS-methyl- PGF methyl ester is saponified to give lS-methyl- PGF infrared absorption at 3260, 2600, 1710, 1365, 1235, 1040, and 970 cmr NMR peaks (deuterochloroform at 5.82, 5.65-5.15 (multiplet), and 4.2-3.8 6; mass spectral molecular ion peaks at 350, 332, and 314.

Also following the procedure of Example 15, l5-methyl-l5(R)-PGF methyl ester is saponified to 15-methyl- 15(R)- PGF infrared absorption at 3250, 2600, 1710, 1235, 1040, and 970 cm.- NMR peaks (deuterochloroform) at 6.15 (singlet), 4.203.8 (multiplet), and 0.90 (triplet).

EXAMPLE 18.15-Methyl-PGF and 15-Methyl-15(R)- PGF Following the procedure of Example 15, the tris-(trimethylsilyl) derivatives of 15-oxo-PGF (5.1 g.) is

reacted with a total of 8 ml. of 3 molar methylmagnesium bromide in diethyl ether, and the product is hydrolyzed to give a mixture of 15-methyl-PGF and 15-methyl-15 (R)-PGF (4.37 g.) in the form of a dark oil. Crystallization of this oil from a mixture of methanol and ethyl acetate, and recrystallization of the resulting crystals from a mixture of the same solvents gives IS-methyI-PGF M.P. 134-l34.5 C.; infrared absorption at 3250, 3180, 2720, 1710, 1345, 1305, 1235, 1085, 1050, 970, and 920 cm.- NMR peaks (dimethylsulfoxide) at 5.46 (doublet), 5.0-4.0, and 3.8 (multiplet) 6; mass spectral molecular ion peaks at 368, 350, 332, 314, 297, 278, and 205.

15-methyl-l5(R)-PGF is obtained from the mother liquors of the above crystallization and recrystallization of IS-methyI-PGF EXAMPLE 19.15-Methyl-PGF and 15-Methyl-15 (R)- PGF Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of 15-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of 15-methyI-PGF and 15-methyl-15 (R)-PGF This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified to give 15-methyl-PGF and 15-methyl-15(R)-PGF as described in Example 15. Alternatively, the mixture of acids is separated as described in Example 16.

EXAMPLE 20.-15-Methyl-PGF and 15-Methyl-15(R)- PGF3,

Following the procedure of Example 15, the tri-(trimethylsilyl) derivative of 15-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of 15-methyl-PGF and 15-methyl-15 (R)-PGF This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively, the mixture of acids is separated as described in Example 16.

EXAMPLE 21 .-Dihydro-15-Methyl-PGF and Dihydro- 15-Methyl-15 (R) -PGF Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of dihydro-IS-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of dihydro-IS-methyl-PGF and dihydro-15-methyl-15(R)-PGF This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively the mixture of acids is separated as described in Example 16.

EXAMPLE 22.-Dihydro-15-Methyl-PGF and Dihydro- 15 -Methyl- 15 (R) -PGF Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of dihydro-l5-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of dihydro-IS-methyl-PGF' and dihydro-15-methyl-15 (R)-PGF This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively, the mixture of acids is separated as described in Example 16.

Following the procedure of Example 15, the methyl, ethyl, tert-butyl, and 2-ethyl-hexyl esters of the bis-(trimethylsilyl) derivatives of 15-oxo-PGF 15-oxo-PGF 15-oxo-PGF2.., 15-oxo-PGF l5-oxo-PGF 15-oxo- PGF dihydro l5 oxo PGF,, and dihydro-15-oxo- PGF are each transformed to the corresponding 15- methyl and 15-methyl-l5(R) esters.

Also following the procedure of Example 15, the racemic forms of the trimethylsilyl derivatives of 15-oxo- PGF 15-oxo-PGF 15-oxo-PGF l5-oxo-PGF 15- oxo-PGFgu, 15-oxo-PGF dihydro-IS-oxo-PGF dihy- 19 dro-15-oxo-PGF and the methyl, ethyl, tert-butyl, and Z-ethylhexyl esters of each of those, tris derivatives of the acids and his derivatives of the esters, are each transformed to the corresponding 15-methyl and 15-methyl-15 (R) acid or ester.

Also following the procedure of Example 15, the tris- (triphenylsilyl) and tris (tribenzylsilyl) derivatives of 15- oxo-PGF l5-oxo-PGF 15-oxo-PGF l5-oxo-PGF 15-oxo-PGF 15-oxo-PGF dihydro-l5-oxo-PGF and dihyd1'0-15-OXOPGF and of the racernic forms of each of those optically active acids, and also the bis-(triphenylsilyl) and bis-(tribenzylsilyl) derivatives of the corresponding methyl, ethyl, tert-butyl, and Z-ethylhexyl esters of each of those optically active and racernic acids are each transformed to the corresponding 15-methyl and 15- methyl-15 (R) acid or ester.

Also following the procedure of Example 15 but using ethylmagnesium bromide in place of the methylmagnesium bromide, the tris-(trimethylsilyl), tris-(triphenylsilyl), and the tris-(tribenzylsilyl) derivatives of l5-oxo- PGF 15-oxo-P'GF l5-oxo-PGFza, 15-oxo-PGF l5- oxo-PGF 15-oxo-PGF dihydro-15-oxo-P'GF1.. dihydro-li-oxo-PGF and the racernic forms of each of those optically active acids, and also the bis-(trimethylsilyl), bis-(triphenylsilyl), and bis(tribenzylsilyl) derivatives of the methyl, ethyl, tert-butyl, and 2-ethylhexy1 esters of each of those optically active and racemic acids are each transformed to the corresponding IS-ethyl and 15-ethyl- 15 (R) acid or ester.

EXAMPLE 23.-lS-Methyl-PGE A solution of IS-methyl-PGl-q (95 mg.) in 40 ml. of acetone is cooled to -10 C. Jones reagent (0.1 ml. of a solution of 21 g. of chromic anhydride, 60 ml. of water, and 17 ml. of concentrated sulfuric acid), precooled to (1., is added wtih vigorous stirring. After minutes at C., thin layer chromatography on silica gel (acetic acidzmethanol:chloroform; 5:5:90) of a small portion of the reaction mixture indicates about 50% reaction completion. An additional 0.06 ml. of Jones reagent is added to the still cold reaction mixture with stirring, and the mixture is stirred an additional 5 minutes at l0 C. Isopropyl alcohol (1 ml.) is added to the cold reaction mixture. After 5 minutes, the mixture is filtered through a layer of diatomaceous silica (Celite). The filtrate is evaporated at reduced pressure, and the residue is mixed with 5 ml. of saturated aqueous sodium chloride solution. The mixture is extracted repeatedly with ethyl acetate, and the combined extracts are washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure. The residue is chromatographed on 20 g. of neutral silica gel, eluting with 50% ethyl acetate in Skellysolve B. Evaporation of the eluates gives 29 mg. of l5-methyl-PGE mass spectral molecular ion peaks at 350, 332, 317, and 261.

EXAMPLE 24.-Methyl-PGE A solution of 15-methyl-PGF (300 mg.) in 100 ml. of acetone is cooled to 35 C. Jones reagent (0.2 ml.) is added with vigorous stirring, and stirring is continued for 15 minutes. At that point, thin layer chromatography on silica gel (acetic acidzmethanolzchloroform; 5:5:90) of a small portion of the reaction mixture indicates about 75% reaction completion. An additional 0.1 ml. of Jones reagent is added to the reaction mixture and stirring is continued at -35" C. for a total reaction time of 45 minutes. Isopropyl alcohol (1 ml.) is added to the cold reaction mixture which is then allowed to warm to 0 C. and is filtered through Celite. The filtrate is evaporated at reduced pressure, and the residue is dissolved in dichloromethane. That solution is washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure. Each 50 mg. of residue is chromatographed on a thin layer plate x 20 cm.; with a 1000, layer of neutral silica gel),

developing twice with the A-IX solvent system. The silica gel areas containing the desired product as shown by small-scale thin layer chromatography are removed from each plate, combined, placed on top of a neutral silica gel column, and eluted through the column with 10% methanol in ethyl acetate. Evaporation of the eluate gives 15-methyl-PGE infrared absorption at 3400, 2650, 1725, 1600, 1460, 1380, 1280, 1250, 1150, 1125, and 1075 cm.- mass spectral molecular ion peaks at 366, 348, 330, and 259.

EXAMPLE 25 .15-Methyl-PGE Following the procedure of Example 24, IS-methyl- PGF is oxidized to 15-methyl-PGE EXAMPLE 26.-Dihydro-l5-Methyl-PGE Following the procedure of Example 24, dihydro-lS- methyl-PGE is oxidized to dihydro-l5-methyl-PGE EXAMPLE 27.l S-Methyl- 15 (R) -PGE Following the procedure of Example 24, 15-methyl-l5 (R)-PGF is oxidized to l5-methyl15(R)-PGE EXAMPLE 28.15-Methyl-l5 (R) -PGE Following the procedure of Example 24, 15-methyl-l5 (R)-PGF is oxidized to l5-methyl-15(R)PGE Following the procedure of Example 24, 15-methyl-15 (R)-PGF3B is oxidized to l5-methyl-15(R)-PGE EXAMPLE 30.Dihydro- 15 (R -PGE Following the procedure of Example 24, dihydro-IS- methyl-15(R)-PGF is oxidized to dihydro-lS-methyl-lS (R)-PGE Following the procedure of Example 24, IS-methyl- PGF 15 methyl-15(R)-PGF l5-methyl-PGF l5- methyl 15 (R)-PGF 15-methyl-PGF 15-methyl-15 (R)-PGF dihydro-15-methyl-PGF and dihydro-lS- methyl-15 (R)-PGF are each oxidized to the corresponding PGE compound.

Also following the procedure of Example 24, the methyl, ethyl, tert-butyl, and Z-ethyl-hexyl esters of lS-methyl- PGF 15 methyl-PGE 15-methyl-l5(R)-PGF 15- methyl 15 (R) PGE 15-methyl-PGF l5-methyl- PGF 15 methyl 15 (R)-PGF 15-methyl-15(R)- PGF 15-methyl-PGF 15-methyl-PGF 15-methyl-15 (R)-PGF 15-methyl-15(R)-PGF dihydro-lS-methyl- PGF dihydro IS-methyl-PGF dihydro-lS-methyl-IS (R)-PGF and dihydro-l5-methyl-15(R)-PGF are each oxidized to the corresponding 15 methyl-PGE or 15 methyl-l5(R)-PGE ester.

Also following the procedure of Example 24, the racernic forms of lS-methyl-PGF IS-methyI-PGF 15- methyl-15(R)-PGF 15-methyl-l5 (R)PGF l5-methyl-PGF 15-methyl-PGF 15-methyl-15(R)-PGF 15- methyl 15(R)-PGF l5-methyl-PGF 15-methyl- PGF 15-methyl-l5(R)-PGF l5-methyl-l5(R)PGF dihydro IS-methyI-PGF dihydro-15-methyl-PGF dihydro 15-methy1-l5(R)-PGF and dihydro-lS-methyl- 15(R)-PGF and the methyl, ethyl, tert-butyl and 2- ethylhexyl esters of each of those racemic acids are each oxidized to the corresponding racemic 15-methyl-PGE or 15-methyl-l5(R)-PGE acid or ester.

Also following the procedure of Example 24, IS-ethyl- PGF IS-ethyI-PGF 15-ethyl-15(R)-PGF IS-ethyl- 15 (R)-PGF IS-ethyl-PGF IS-ethyl-PGF 15-ethyl- 15 (R)-PGF l5-ethyl-15(R)-PGF 15-ethyl-PGF 15- ethyl PGF 15 ethyl-15(R)-PGF 15-ethyl-15(R)- PGF dihydro IS-ethyl-PGF dihydro-lS-ethyl-PGF dihydro 15-ethyl-l5(R)-PGF dihydro-l5-ethyll5(R)- PGF and the racernic forms of each of those optically active acids, and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those optically active and racernic acids are each oxidized to the corresponding 15-ethyl- PGE or 15-ethyl-15 (IQ-PGE acid or ester.

21 I claim: 1. An optically active compound of the formula:

or a racemic compound of that formula and the mirror image thereof, wherein X and Y are both -CH CH or wherein X is transCH=OH- and Y is CH CH or cisCH=CI-I, wherein A is alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one or 2 fiuoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, wherein R is alkyl of one to 8 carbon atoms, inclusive, or -Si(A) wherein A is as defined above, and wherein indicates attachment of (A) -.SiO to the ring in alpha or beta configuration.

2. A compound according to claim 1 wherein A is methyl and R is --Si-(A) 3. An optically active compound according to claim 2.

4. A compound according to claim 3 wherein indicates an alpha attachment of (A) SiO to the ring.

5. A compound according to claim 4 wherein X and Y are both CH CH 6. A compound according to claim 4 wherein X is transCH=CH and Y is -OH CH 7. A compound according to claim 4 wherein X is transCH=OH- and Y is cisCH=CH.

8. A racemic compound according to claim 2.

9. A compound according to claim 8 wherein indicates an alpha attachment of (A) Si-O- to the ring.

10. A compound according to claim 9 wherein X and Y are both -CH CH 11. A compound according to claim 9 wherein X'is trans-CH=CH and Y is CH CH 12. A compound according to claim 9 wherein X is trans-CH=OH and Y is cisCH=CH.

13. An optically active compound of the formula:

(A)aSl-O urn-st- 0 or a racemic compound of that formula and the mirror image thereof, wherein A is alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phcnyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, wherein R is alkyl of one to 8 carbon atoms, inclusive, or Si(A) wherein A is as defined above, and wherein indicates attachment of (A) Si-O- to the ring in alpa or beta configuration.

14. A compound according to claim 13 wherein R, is Si(A) and A is methyl.

15. An optically active compound according to claim 14.

16. A compound according to claim 15 wherein indicates an alpha attachment of (A) Si-O to the ring.

17. A compound according to claim 15 wherein indicates a beta attachment of (A) Si-O to the ring.

18. A racemic compound according to claim 14.

19. A compound according to claim-18 wherein indicates an alpa attachment of (A) SiO- to the ring.

20. A compound according to claim 18 wherein indicates a beta attachment of (A) SiO- to the ring.

References Cited UNITED STATES PATENTS 3,455,992 7/1969 'Bagli et al. 260-468 D 3,651,116 3/1972 Lincoln et a1. 260448.8 R 3,644,502 2/ 1972 Morin et a1. 260514 R 3,532,721 IO/1970 Finch 260 468 D X 3,538,120 11/1970 Finch 260-468 D X DANIEL E. WYMAN, Primary Examiner P. F. SHAVER, Assistant Examiner US. Cl. X.R.

260-468 D, 468 R, 514 R UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,77 ,7 DATED November 6, 1975 lNVENTOR(S) Gordon L. Bundy it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col umn l, l i ne 31, "whi ch the fol lowi ng" should read which has the following Column 2, line 10, formula V should appear as shown below i nstead of as i n the patent,

Col umn 6, l i ne 2 PFG should read PGF Column 10, l i ne 9, (CH shoul d read (CH Column 11, l i ne l2, "PGF and PGF" shoul d read PGF and PGF i i ne 24 "PGE should read PGFs Coi umn 14, l i ne l -l, "Example, PGFg should read Example 1, PGF line 73, "PGE should read PGF 1a Col umn 15, l i ne "deri vatives" should read derivative --a Column 16, line 6, "tris-(trimethyl should read tris-(trimethylsi lyl Column 17, line 75, "derivatives" should read derivative Column 18, line 69, "PGF should read PGF Signed and sealed this 24th day of June 1975.

JZLnL) Attest Q C MARSHALL DAM: RUTH C. Z-KASON Commissioner of Patents Arresting Officer and Trademarks 

